Surplus fatty acid synthesis increases oxidative stress in adipocytes and induces lipodystrophy
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Published:2024-01-02
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Weng Li, Tang Wen-Shuai, Wang Xu, Gong YingyunORCID, Liu ChangqinORCID, Hong Ni-Na, Tao Ying, Li Kuang-Zheng, Liu Shu-Ning, Jiang Wanzi, Li Ying, Yao KeORCID, Chen LiORCID, Huang HeORCID, Zhao Yu-ZhengORCID, Hu Ze-PingORCID, Lu Youli, Ye Haobin, Du Xingrong, Zhou HongwenORCID, Li PengORCID, Zhao Tong-JinORCID
Abstract
AbstractAdipocytes are the primary sites for fatty acid storage, but the synthesis rate of fatty acids is very low. The physiological significance of this phenomenon remains unclear. Here, we show that surplus fatty acid synthesis in adipocytes induces necroptosis and lipodystrophy. Transcriptional activation of FASN elevates fatty acid synthesis, but decreases NADPH level and increases ROS production, which ultimately leads to adipocyte necroptosis. We identify MED20, a subunit of the Mediator complex, as a negative regulator of FASN transcription. Adipocyte-specific male Med20 knockout mice progressively develop lipodystrophy, which is reversed by scavenging ROS. Further, in a murine model of HIV-associated lipodystrophy and a human patient with acquired lipodystrophy, ROS neutralization significantly improves metabolic disorders, indicating a causal role of ROS in disease onset. Our study well explains the low fatty acid synthesis rate in adipocytes, and sheds light on the management of acquired lipodystrophy.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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